Progesterone, Glial Aging, and Alzheimer Disease In this Program Project we jointly propose to examine the effects of progesterone (P4) and estrogen (E2) on synaptic plasticity in rodent brain. In this project, we hypothesize that progestogens directly regulate glial activities via progesterone receptor/s and via interactions with E2-dependent pathways. We will examine effects of P4, and selected progestogens including medroxyprogesterone (MPA), on glial support of neurite sprouting and repair. Pilot data show P4 supported neurite sprouting in astrocyte/neuron co-cultures. However, when microglia were added to the co-culture (mixed glia/neuron), P4 did not support sprouting and reduced neuron survival. Moreover, P4 attenuated E2-dependent sprouting in mixed glia/neuron co-cultures. These observations suggest that P4 may regulate microglial-mediated inflammatory mechanisms. Because aging also influences sprouting and inflammation, we will examine the role of glial age in P4-E2 interactions, using in vivo and in vitro models for aging and Alzheimer's Disease (AD). New in vivo models for hormone therapy (HT) will be developed including perimenopausal and postmenopausal equivalents in the rat and in the triple transgenic AD mouse. In the perimenopausal model, HT will be given to middle-aged female rats characterized by irregular cycles. The menopausal model will address one of the critical questions in human HT - is HT effectiveness dependent on the lenght of time after menopause that HT is begun? These newly developed models will provide insight into the basic mechanisms underlying the effects of HT. In vitro models will include glial-neuron co-cultures of "wounding-in-a-dish" and glial-induced neurotoxicity, using glia derived from adult rat brains of different ages.